A 45 year old mother of three, with dyspnea and fatigue

Upon physical examination she remained unaffected without any signs of decompensated heart failure. Her blood pressure was 120/80 mmHg and auscultation of heart and lungs was entirely normal.
Her ECG demonstrated sinus rhythm with a frequency of 44 bpm and a wide left bundle branch block with a QRS width of 140ms (Figure 1).
Echocardiography revealed a dilated left ventricle with an end diastolic diameter of 59 mm and impaired systolic function with an ejection fraction of 30 %. There was a mild regurgitation of the mitral valve and the left atrium was dilated with a diameter of 45 mm. No other abnormalities were recorded by echocardiography (Figure 2).
Chest X-ray showed a slight increase in cardiac diameter and otherwise normal conditions. A coronary angiography was carried out and demonstrated normal coronary arteries.

The patient had 3 children.
Her oldest daughter was 24 years of age. Her clinical examination revealed delayed muscular relaxation following contraction in forearms and hands. She showed no signs of decompensated heart failure and her ECG and Echocardiogram was normal. She had recently given birth to a boy who was delivered prematurely at 34 weeks of the pregnancy because of polyhydramnion. Upon delivery the newborn son was hypotonic with respiratory failure and bradycardia. He was successfully resuscitated and put on a ventilator for a few days. In the following weeks it was noted that he had few spontaneous movements of his limps and diminished facial expression. In addition his facial features were abnormal with hypertelorism, a receding chin and a tent-shape mouth. He had a normal ECG and Echocardiogram.
Her son aged 19 years had motor and language difficulties and was mentally handicapped. He went to a school for children with special needs. He showed no clinical signs of decompensated heart failure. His ECG was abnormal and demonstrated sinus rhythm and incomplete left bundle branch block with a QRS width of 142 ms (Figure 3).

Her youngest daughter was delivered prematurely at 28 weeks of the pregnancy because of polyhydramnion. She had a birth weight of 900 g and died of respiratory failure one week later.

QUESTIONS:

1. What could be the explanation of the disease presentation of the patient?
2. Would it be relevant to perform further investigations, blood tests or involve other specialties than cardiology in the diagnosis of the family?

Answers:

Question 1. What could be the explanation of the disease presentation of the patient?

The index patient had severe dilated cardiomyopathy(DCM) without other obvious symptoms or signs of systemic disease. However, family investigation revealed a far more complex disease presentation.
The patient´s son had slight impaired LV function and an abnormal ECG. In addition he had mild skeletal muscle impairment and was mentally handicapped. The daughter had a normal cardiac examination, but significantly impaired skeletal muscle relaxation of upper extremities. She gave birth to a son with syndromic features, hypotonia, respiratory failure and impaired LV function.
Overall, the co-existence of DCM, mentally retardation, respiratory failure, polyhydramnion, syndromic features and musculoskeletal symptoms in the family, made the diagnosis of dystrofia myotonica(DM) most likely. This was further supported by the fact that the disease expression became more severe in the offspring of the proband(genetic anticipation).
DM is characterized by myotonia, muscular dystrophy and weakness, impaired cognitive functions, learning disabilities, cataracts, heart disease and endocrine changes, mainly diabetes and hypogonadism.
Cardiac involvement includes ventricular dysfynction, ECG abnormalities, conduction system disease, tachyarrhythmias and sudden cardiac death (1).
Two types of DM have been described. Type 1 (DM1) most commonly shows distal muscular involvement and exists in a severe congenital form and a milder childhood-onset form. Type 2 (DM2) most often shows proximal muscular involvement and generally manifests with milder signs and symptoms. Diagnosis is based on repeat expansions on the DMPK gene for DM1 and the ZNF9 gene for DM2.
The gene DMPK is located on the human chromosome 19q and encodes the enzyme dystrophia myotonica protein kinase. Repeating CTG triplets in the non-translated part of the gene is associated with DM1(2). The pathogenic mechanism is not fully understood, but alterations manifests on RNA level and lead to a decrease in DMPK mRNA and protein.
In healthy individuals the DMPK gene contains 5-37 copies of the CTG trinucleotide, whereas expansion to 50-5.000 copies is diagnostic of DM1(3). There is a direct relationship between the number of CTG copies and the severity of the condition(4).
DM1 shows autosomal dominant inheritance. A characteristic feature is anticipation, implying that the CTG expansion increases with each generation, causing earlier onset and more severe phenotype. Genotype positive mothers generally passes on larger CTG expansions to their offspring, whereas the amplification rarely expand significantly in the transmission from a genotype positive father to his offspring. Hence, children with genotype positive mothers are at higher risk of severe disease and early onset.
The index patient II-5 underwent genetic investigation of the DMPK gene associated with DM1 and a trinucleotide CTG repeat expansion mutation with 120 CTG repeats were identified. Her son III-3, daughter III-2 and grandson IV-1 were all genotype positive with 1050, 520 and 1050 CTG repeats respectively.
The family pedigree is illustrated below.

Question 2.Would it be relevant to perform further investigations, blood tests or involve other specialties than cardiology in the diagnosis of the family?

Clinical examination, DNA analysis and family investigation are the most important studies in relation to diagnosis. However, creatine kinase(CK) measurement, electromyography(EMG) and muscle biopsy should be considered in the diagnose.
DM1 is manifested as a multi systemic disease and it is therefore necessary to involve several specialties in the diagnosis, follow-up and treatment of patients.
The index patient received medical anticongestive treatment. Since DM1 patients have a significantly higher occurrence of AV-conduction abnormalities, tachyarrhythmia and sudden cardiac death(5), the proband received a DDD-ICD.
Adult DM1 patients usually develop cardiac manifestations after they develop neuromuscular symptoms. Hence regular cardiac screening and monitoring including clinical examination, ECG and echocardiography is advisable in all DM1 patients.
The family was referred to genetic counseling.
Affected family members were assigned to a neurologist for individual assessment and monitoring of neuromuscular symptoms. A blood sample screening for endocrine disorders including diabetes were carried out, and patients were referred to an endocrinologist for evaluation and follow up. Finally patients were examined for cataract by an ophthalmologist.

Conclusion:

In conclusion family investigation is very important, even when the disease presentation seems simple. In some cases family history is crucial for diagnosis and treatment.